MicroRNAs (miRNAs) are short (about 21-24-nucleotides) noncoding RNAs that are thought to regulate gene expression through sequence-specific base pairing with target mRNAs. The underlying mechanism is still poorly understood, but it appears to involve the inhibition of translational initiation.
Many of the functional roles of microRNAs hint at the potential involvement of microRNAs in human disease, and as major regulators of growth and proliferation. As many microRNAs are de-regulated in primary human tumours, a role of microRNAs in human cancers has been suggested. Accordingly miRNA deficiencies or excesses have been correlated with a number of clinically important diseases ranging from myocardial infarction to cancers.
Potential roles of microRNAs in the development as well as the regulation of the immune system have also been suggested.
Inflammation, a key component of the immune system, functions in both defense (physiological) and in pathophysiological events to maintain the homeostasis of tissues, organs and individual cells. Acute inflammation is a short-term process characterized by the classic signs of inflammation, i.e. swelling, redness, pain, heat, and loss of function, due to infiltration of tissues by plasma of several activated components such as interleukins, antibodies, hormones etc. and leukocytes. It occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed. Chronic inflammation is a pathological condition characterized by concurrent active inflammation, tissue destruction, and attempts at repair. Chronically inflamed tissue is characterized by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, dendritic cells and other plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
Without inflammation, wounds and infections would not be able to heal and progressive destruction of the tissue would threaten the survival of the organism. Inappropriate inflammation, on the other hand, can lead to various diseases, including but not limited to indications such as hay fever, atherosclerosis, neurodegenerative diseases such as Alzheimer's, cancer and rheumatoid arthritis. For these reasons, inflammation is tightly regulated by the body.
Mononuclear immune cells are under infectious conditions attracted to the site of infection in an attempt to eliminate the foreign pathogen through phagocytosis. Leukocytes and dendritic cells are here activated by the pathogens to synthesize and release proinflammatory cytokines such as IL-1α, IL-1β, IL-3, IL-5, IL-6, IL-8, TNF-α(tumor necrosis factor-α), GM-CSF (granulocyte-macrophage colony-stimulating factor), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), and MCP-I (monocyte chemotactic protein-1). These released cytokines then further attract more immune cells to the infected site, amplifying the response of the immune system to defend the host against the foreign pathogen.
Dendritic cells are derived from hemopoietic bone marrow progenitor cells. These progenitor cells initially transform into immature dendritic cells. These cells are characterized by high endocytic activity and low T-cell activation potential. Immature dendritic cells constantly sample the surrounding environment for foreign pathogens. This is done through pattern recognition receptors such as the toll-like receptors (TLRs), which recognize specific chemical signatures found on subsets of pathogens. Once they have come into contact with a presentable antigen, they become activated into mature dendritic cells and begin to migrate to the lymph node. Immature dendritic cells phagocytize pathogens and degrade their proteins into small pieces and upon maturation present those fragments at their cell surface using MHC molecules. Simultaneously, they upregulate cell-surface receptors that act as co-receptors in T-cell activation. Once in the lymph nodes they act as antigen-presenting cells, in activating helper T-cells and killer T-cells as well as B-cells by presenting them with antigens derived from the pathogen, together with non-antigen specific co-stimulatory signals.
The biological role and in vivo functions of most mammalian miRNAs are still poorly understood and the underlying mechanisms of why and how miRNAs become deregulated are largely unknown.
Glucocorticoids (also referred to as “corticosteroids” or “steroidal drugs”) as well as Nonsteroidal Antiinflammatory Drugs (NSAIDs) represent today one of the most effective clinical treatment for a range of inflammatory conditions, including acute inflammation. However, these drugs can have side effects that may threaten the overall health of the patient.
There remains a need to develop a safe, effective method of treating autoimmune diseases, inflammatory disorders, and cancers or other indications associated with abnormal cell growth or cell division. The present invention provides compositions and methods for treating such diseases and disorders.